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4 Role of the Circadian Clock in the Skin’s Response to Endogenous and External Stressors

4 Role of the Circadian Clock in the Skin’s Response to Endogenous and External Stressors

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the absence of the clock. These findings are corroborated by previous studies in

Bmal1−/− mice showing that they have elevated levels of ROS (Stringari et al. 2015;

Geyfman et al. 2012). High ROS levels present during S-phase might contribute to

the deleterious phenotypes seen in circadian knockout mice including reduced

lifespans (Libert et al. 2012) and various symptoms of premature aging (Kowalska

et al. 2013; Kondratov et al. 2006; Khapre et al. 2011). The involvement of elevated

ROS in the premature aging phenotypes of Bmal1−/− mice is supported by a study

showing that antioxidants could assuage the age-dependent weight loss and development of cataracts typically seen in Bmal1−/− mice (Kondratov et al. 2009).

Interestingly, some of the aging phenotypes in Bmal1−/− mice, including the hair

regrowth defect, require Bmal1 to be ablated early in development before the clock

machinery has matured, suggesting a potential non-circadian role of BMAL1 during

development (Yang et al. 2016).

Apart from its detrimental effects, ROS also function as signaling molecules that

regulate biological activities (Finkel 2011). ROS are implicated in regulating normal homeostatic maintenance in other stem cell niches (Le Belle et al. 2011). The

question as to whether these signaling functions of ROS are regulated by the clock

in epidermal progenitor cells remains unanswered.



14.4.2 Circadian Clock Control of the Unfolded Protein

Response

In response to stressful conditions such as wounding, infections, UV exposure,

hypoxia, nutrient deprivation and ROS accumulation, cells upregulate proteins that

help prevent the accumulation of misfolded proteins in the endoplasmic reticulum;

this response is called the Unfolded Protein Response (UPR). For example, the

UPR is activated in proliferating fibroblasts during wound healing (Matsuzaki et al.

2015). Although the UPR is most commonly thought of as a response to perturbation, it is activated in differentiating keratinocytes of the skin in the most differentiated layers of the epidermis (Sugiura 2013). Interestingly, in mouse skin,

several mRNAs encoding UPR-associated proteins oscillate diurnally, with most of

them exhibiting peak expression in the late night/early morning (Fig. 14.3a). One of

these genes, HERPUD1 is affected in Bmal1−/− mice. Although no studies to date

have investigated the functional significance of the diurnal expression of components of the UPR in the skin, studies in the liver have shown that circadian UPR

activation is coordinated with the timing of maximum protein secretion in mouse

liver (Cretenet et al. 2010; Mauvoisin et al. 2014). Moreover, Cry1−/−; Cry2−/−

mice exhibit dysregulation of endoplasmic reticulum-resident enzymes and perturbed lipid metabolism (Cretenet et al. 2010), suggesting a direct clock role in

modulating the UPR in the liver. The potential role of the circadian clock in

modulating the UPR in the skin is unknown and merits further investigation.



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Fig. 14.3 Circadian expression of stress response pathways in the skin. Heat maps showing the

expression of genes in the skin over 2 days based on previously published whole skin microarrays

performed in mice (Geyfman et al. 2012). The MSigDB database was used to identify significantly

enriched stress response pathways. Shown are diurnal genes associated with unfolded protein

response (a), hypoxia response (b), UV response (c), and xenobiotic response (d). Asterisks

indicate genes whose expression is significantly different in the skin of Bmal1−/− versus wildtype

mice (Geyfman et al. 2012), suggesting the possibility of direct clock regulation



14.4.3 Response to Wounding

The skin has evolved highly effective regenerative mechanisms to close wound

defects. The review of wound healing is beyond the scope of this chapter but suffice

to say, complicated signaling networks that are activated in response to wounding

promote closure of the wound through enhanced migration and proliferation of

fibroblasts and keratinocytes. In addition, polarizing immune cells are recruited to

the wound to clear up debris and kill off intruding microbes. Studies suggest that the

clock facilitates proper wound healing as evidenced by less epithelial coverage and

decreased fibroblast proliferation after wounding in Bmal1−/− mice (Kowalska et al.



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2013). It is possible that healing defects observed in Bmal1−/− mice are at least

partially related to the dampened ability of Bmal1−/− keratinocytes to respond to

pro-proliferative signals in older mice (Janich et al. 2011).

The microenvironment of wounded tissues is hypoxic and has impaired nutrient

supply due to vascular perturbation and high oxygen utilization by cells at the

wound edge (Pai and Hunt 1972). Hypoxia induces the expression of heat shock

proteins, which facilitate epithelial cell migration, thus contributing to

re-epithelialization. The mRNA levels for heat shock proteins (Hsp90 and Hsp70),

as well as several other proteins involved in the response to hypoxia, exhibit diurnal

expression rhythms in mouse skin under homeostasis (Fig. 14.3b).



14.4.4 UVB- and c-Irradiation-Induced DNA Damage

Intricately linked to the cell cycle, the susceptibility to UVB-induced DNA damage

in mouse skin exhibits a diurnal rhythm. UVB-induced DNA damage in the form of

(6-4) photoproducts and cyclobutane pyrimidine dimers is greater when UVB is

applied at night compared to the day. This effect may be explained at least in part by

the diurnal expression of a rate-limiting protein essential for the nucleotide excision

repair pathway, Xeroderma pigmentosum complementation group A (XPA)

(Cleaver 1968), which is lowly expressed in mouse skin during the night compared

to day. The stage of the cell cycle may also contribute to this effect, as DNA is most

vulnerable to damage during the S-phase of the cell cycle (Pantazis 1980), which

also peaks during the night in epidermal progenitors (Geyfman et al. 2012).

Recently, other physiological aspects of the mouse skins’ response to UVB-induced

damage, including sunburn apoptosis, inflammatory cytokine production, and

erythema were found to be time-of-day dependent, with maximal response induced

by UVB exposure at night (Gaddameedhi et al. 2015). Most strikingly, the same

group found that UVB-induced squamous cell carcinomas accrue more rapidly in

mice exposed to UVB at night (Gaddameedhi et al. 2011). Notably, in mouse skin

under homeostasis, multiple mRNAs encoding proteins in the “response to UV”

gene set exhibit diurnal oscillations, suggesting the possibility that other genes play

a role in the diurnal UVB response (Fig. 14.3c). These findings are all in nocturnal

mice, which have opposite phase of the circadian clock compared to diurnal

humans where the maximum sensitivity to UVB-induced DNA epidermal damage

may be during the day, the time of maximum solar exposure (Geyfman et al. 2012;

Gaddameedhi et al. 2011).

Studies have shown that cells in the M phase are most susceptible to

c-irradiation-induced DNA damage (Sinclair and Morton 1965; Terasima and

Tolmach 1961). Consistent with this fact, c-irradiation causes more extensive hair

loss when applied to skin during the early morning versus in the afternoon (Plikus

et al. 2013). Cry1−/−; Cry2−/− mice, which are arrhythmic, exhibit similar and

enhanced levels of hair loss in response to c-irradiation regardless of time of day,

implicating a role for the circadian clock in this process (Plikus et al. 2013).



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Together, these studies support a role for the circadian clock in modulating the

epidermal response to exogenous stressors in the form of UVB- and c-irradiation

radiation.



14.4.5 Antioxidant Defense

The skin possesses an intricate network of antioxidant mechanisms poised to

assuage oxidant stress caused by exposure to solar radiation, chemicals, inflammation, and endogenous metabolic processes. Antioxidant systems in the skin

include proteins that protect against ROS, such as catalase (CAT), glutathione

peroxidase (GPx), and superoxide dismutase (SOD), as well as antioxidants like

vitamins A, C, and E, melatonin, and glutathione (GSH). Many of these components exhibit diurnal rhythmicity throughout the body. For example, Melatonin,

most well known for its role as a primary circadian effector hormone, is also a

potent ROS- and NOS-scavenger. The structure of melatonin allows it to neutralize

many forms of radicals such as H2O2, ÁOH, singlet oxygen (1O2), superoxide anion

(ÁO2−), peroxynitrite anion (ONOO−) and peroxyl radical (LOOÁ) (Tan et al. 2002).

The neutralization of these oxidizing molecules is especially important for skin

health due to the epidermis’ high rate of cell proliferation, which correlates with its

propensity to become cancerous (Tomasetti and Vogelstein 2015). Apart from its

direct actions, melatonin also works in the skin by inhibiting the depletion of

antioxidant enzymes including CAT, GPx, and SODs after UV radiation-mediated

photodamage (Fischer et al. 2013).

Another mechanism by which the skin and other organs fight the accumulation

of harmful free radicals is through the action of SODs, which catalyze the dismutation of O2− into O2 and H2O2. SODs are integral to skin homeostasis, as

heterozygous deletion of SOD2 results in an “immune-ageing” phenotype, with

enhanced T cell-mediated contact hypersensitivity (Scheurmann et al. 2014) as well

as nuclear DNA damage, and cellular senescence in the mouse epidermis (Velarde

et al. 2012). SODs are expressed in a diurnal manner in many tissues including rat

intestine, lung, and cerebellum (Martin et al. 2003). Per2 mutant mice show

dampened SOD expression levels in the liver, while Per1/2 double knockout mice

have a shift in phase of SOD gene expression (Jang et al. 2011), suggesting that this

mechanism is modulated by the circadian clock.

GSH is a critical antioxidant that neutralizes ROS in a process catalyzed by GPx

proteins, in which GSH becomes oxidized to form glutathione disulfide (GSSG).

GSH and GSSG, as well as other components of the GSH pathway, such as GPx,

GR, and GST, are robustly diurnal in multiple tissues (Baydas et al. 2002a; Lapenna

et al. 1992; Maurice et al. 1991) with a peak expression of GSH during the light

phase in mice and during the night in humans (Atkinson and Babbitt 2009). A few

Glutathione S-transferases, including GSTT1 and GSTA3, exhibit diurnal rhythmicity in their mRNA expression in the skin and are altered in Bmal1−/− mice

(Geyfman et al. 2012). Although there are no studies to date investigating the



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physiological significance of the circadian rhythmicity of these GSH-associated

genes in the skin, higher oxidized GSH levels are often seen in lesional and

non-lesional skin from patients with chronic irritant dermatitis, suggesting this

pathway is integral for maintaining skin homeostasis (Kaur et al. 2001).



14.4.6 Xenobiotic Detoxification

The skin protects against the effects of man-made genotoxic drugs and cytotoxic

compounds found in nature. The Aryl hydrocarbon receptor (AhR) is a

ligand-dependent transcription factor that plays a critical role in metabolism of

small molecules, including dioxins, polycyclic aromatic hydrocarbons, plant

polyphenols, and tryptophan photoproducts (Rannug and Fritsche 2006). Upon

ligand binding, AhR translocates to the nucleus and dimerizes with ARNT,

inducing transcription of xenobiotic-metabolizing enzymes, including cytochrome

P450 (CYP) 1A1 and CYP1A2/B1. The CYP proteins then degrade chemical toxins

and, as a by-product, produce ROS. AhR also activates the expression of nuclear

factor-erythroid 2-related factor-2 (Nrf2), which regulates the expression of myriad

of antioxidant proteins including NAD(P)H dehydrogenase [quinone] 1 (Nqo1) and

Heme oxygenase 1 (HO-1) that protect against genotoxicity due to elevated ROS

(Cho et al. 2002). In the mouse lung epithelium, circadian Nrf2 levels control the

pulmonary response to oxidative injury in a lung fibrosis model, with greater

fibrosis accruing during the early evening, corresponding to lowest Nrf2 levels

(Pekovic-Vaughan et al. 2014). Moreover, reduced Nrf2 and GSH expression in the

lungs of ClockD19 mice is linked to increased oxidative damage of proteins and

spontaneous development of fibrosis in the airways (Perovic-Vaughan et al. 2014).

In the mouse skin, the expression of Nrf2, Nqo1, and HO-1 is diurnal with a peak in

expression a few hours prior to the onset of night; in addition, Nqo1 and Nrf2

mRNA expression is altered in Bmal1−/− mice (Geyfman et al. 2012), suggesting

these genes are controlled by the CLOCK:BMAL1 complex.

The AhR pathway and the circadian clock exhibit a dynamic, reciprocal interaction. On the one hand, AhR expression and DNA binding activity have a 24-h

rhythmicity; core clock proteins regulate AhR-mediated enzyme expression and

detoxification activity in the rat pituitary and liver (Huang et al. 2002; Tanimura

et al. 2011). On the other hand, activation of the AhR pathway by dioxins impacts

the expression of core clock genes in mouse liver and hematopoietic stem cells (Xu

et al. 2010). It is currently unknown whether this disruption occurs in epidermal and

follicular progenitor cells. However, if it does, this would suggest yet another

pathway by which dioxins (acting through AhR activation) exert their damaging

effects on the skin.

AhR is expressed in the upper part of the hair follicle including the infundibulum

(Ikuta et al. 2009). Although the mRNA expression of AhR itself is not circadian in

mouse skin, transcripts for genes associated with the xenobiotic response such as

CYP2E1 and epoxide hydrolase 1 exhibit diurnal rhythmicity, peaking around the



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onset of night in mouse skin under homeostasis (Geyfman et al. 2012) (Fig. 14.3d).

The functional significance of the circadian regulation of xenobiotic metabolism

within the skin may be to prepare for and/or respond to chemical toxins encountered

during the night, when mice are most active.



14.5



Circadian Regulation of Skin Immunity



14.5.1 Circadian Rhythm in Skin Innate Immunity

In addition to the barrier mechanisms described above, a diverse army of inflammatory cells in the skin deals with environmental insults by reacting, attacking, and

relaying danger signals to the rest of the body. Epidermal keratinocytes, which

compose the bulk of cells in the skin, secrete antimicrobial defensin peptides to

resist pathogenic microbial colonization. Defensin b23 mRNA exhibits a striking

circadian rhythmicity in mouse skin under homeostasis (Geyfman et al. 2012). Skin

immunity also relies on evolutionarily conserved pattern recognition receptors

(PRRs), including TLR 1, 2, 3, 5, 9 and 10, which enable innate inflammatory

responses to a variety of immunogenic stimuli including bacterial, fungal, viral, and

apoptotic molecules (Miller et al. 2005; Köllisch et al. 2005; Lebre et al. 2007).

Skin-resident leukocytes derived from the hematopoietic system contribute to

barrier defense, expressing a diverse array of PRRs, including TLRs 1-10 (Renn

et al. 2006) and C-type lectin receptors. In healthy mouse whole skin, TLR 4, 7, 8,

and 9 expression oscillates diurnally (Geyfman et al. 2012). PRR engagement

induces nuclear translocation of inflammatory transcription factors, including

nuclear factor jB (NF-jB), enabling pro-inflammatory gene expression. The circadian clock regulates the magnitude of these inflammatory responses following

PRR engagement. The most profound example of the circadian regulation of PRR

sensitivity is exhibited by the increased mortality following systemic lipopolysaccharide (LPS) administration immediately preceding or during the evening in mice;

this effect is clock-dependent as Per2 mutant mice are resistant to LPS-induced

endotoxic shock (Liu et al. 2006). LPS is a microbial component of gram-negative

bacteria which induces inflammatory cytokine secretion through activation of

TLR4, and systemic administration results in endotoxic shock and sepsis. Results in

mouse LPS models are recapitulated in human sepsis, in which greater mortality is

observed during the night (Smolensky et al. 1972).

Immune cell sensitivity to pathogenic challenges is regulated by the circadian clock

in numerous epithelial barriers. Lung epithelium responds diurnally to challenge by

LPS or S. pneumoniae, where inflammatory chemokine release and neutrophil

recruitment peaks during the early day in mice (Gibbs et al. 2014). This diurnal

variation in reactivity to exogenous particulates in the lung epithelium may contribute

to the potent early morning symptoms of wheezing in asthma patients (Barnes 1985)

and decreased lung function in COPD patients (Calverley and Walker 2003). In

addition, the ability of the gut epithelium to respond to, and defend against, ingested



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microbes is dependent on the circadian expression of defensins (Froy et al. 2005) and

PPRs in intestinal epithelial cells that both peak at the intersection between late night

and early day (Mukherji et al. 2013). The physiological outcome of the circadian

regulation of these proteins was revealed in experiments where investigators fed mice

with Salmonella, and found that mice infected during the day showed increased

colonization levels and pathology scores compared to nighttime-infected mice (Bellet

et al. 2013). These findings support the idea that the circadian clock in epithelia

promotes immunity during night, when mice are active and feeding, and thus most

likely to encounter pathogenic microorganisms.



14.5.2 Circadian Rhythm in Skin Adaptive Immunity

In addition to innate PRR-mediated immunity, the skin epithelium is home to a

complex network of leukocytes which also permit adaptive humoral and

cell-mediated immunity (Pasparakis et al. 2014). Allergic contact dermatitis occurs

in the skin following exposure to environmental chemicals, e.g. poison ivy,

resulting in delayed type hypersensitivity (DTH). DTH is a cell-mediated response,

requiring leukocyte migration to the lymph nodes and antigen presentation by

skin-resident macrophages and dendritic cells to T cells. DTH has become a

favorite animal model for human chronic inflammatory disease as the inflammatory

pathology that occurs in skin DTH mirrors numerous cellular processes which also

occur in chronic autoimmune disease in multiple organs. Prendergast et al. (2013)

found that circadian trafficking of antigen presenting CD11c+ dendritic cells in

response to DTH became arrhythmic after a disruptive phase shift (DPS) procedure.

Psoriasis, a common chronic human autoimmune disease affecting 2 % of the

population, is characterized by increased epidermal proliferation, epidermal thickening, altered epidermal differentiation, and organized lymphoid infiltrates in the

reticular dermis. Psoriasis pathology is thought to be initiated by immuno-triggering

environmental exposures and infections in patients with susceptibility to immune

de-regulation due to genetic risk factors (reviewed in Harden et al. 2015). Innate

immune cells such as dendritic cells expressing PRRs become activated to migrate to

lymph nodes where they stimulate the differentiation of T cells into inflammatory

subsets which become competent to enter the skin. T cell cytokine and growth factor

secretion in the skin alters the transcriptional profile of keratinocytes and endothelial

cells, resulting in a hyperproliferative state and self-perpetuating chronic inflammatory responses. The diurnal rhythmicity of psoriasis immunopathology was first

published in the 1980s where Pigatto et al. (1985) found a substantial diurnal

rhythmicity in neutrophil recruitment to the psoriatic lesions.

Work with psoriasis animal models suggests a circadian regulation of skin

immunopathology. The psoriasiform lesion-inducing drug Imiquimod (IMQ)



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functions as a pathogen-associated molecular pattern (PAMP) and activates TLR7

signaling in skin-resident dendritic cells, resulting in the influx of inflammatory

cells, proinflammatory cytokine secretion, and epidermal alterations (acanthosis, parakeratosis) similar to human psoriasis. These symptoms are more pronounced when mice are treated with IMQ at night than during the day (Ando et al.

2015). Knockout studies and circadian disruption studies support the modulatory

role of the circadian clock in maintaining proper immune responsiveness to external

PAMPs and antigens. Mice with mutated Clock genes have damped psoriatic lesion

formation in response to IMQ, while Per2 knockout mice have exacerbated

pathogenesis (Ando et al. 2015). In other studies, mice subjected to disrupted

lighting cycles and treated with the psoriatic-inducing agent human neutrophil

elastase developed exacerbated psoriatic histopathology and pro-inflammatory

cytokine production compared to mice housed under normal 12L:12D conditions

(Hirotsu et al. 2012).

Nocturnal pruritus, or increased itchiness at night, has been well described in

patients with various dermatological disorders, including psoriasis (Yosipovitch

et al. 2000), atopic dermatitis (Yosipovitch and Tang 2002), lichen simplex

chronicus (Koca et al. 2006), and scabies (Chouela et al. 2002). There are many

factors that may contribute to this effect, one of them being histamine release by

mast cells, which is modulated by the circadian clock (Baumann et al. 2013).

Time-of-day–dependent variations in a mouse model of IgE/mast cell–mediated

allergic reaction (passive cutaneous anaphylactic (PCA) reaction) peaked during at

night. Furthermore, these rhythms in reactivity were reliant on a functional clock

protein, Per2 (Nakamura et al. 2011). Together, these studies illustrate the powerful

modulatory role of the circadian clock on immune responses in the skin.



14.6



Conclusions and Opportunities for Chronotherapy



Our skin maintains a dynamic barrier, protecting us from harmful external stimuli

like fluctuating temperatures, humidity levels, UV rays, pollution, and infections.

Work on the role of the circadian clock in skin suggests that it has evolved to

coordinate the skins’ protective function with changes in the external environment,

allowing for optimal response to external insults. The clock also functions to

temporally gate internal cellular processes such as oxidative phosphorylation, cell

division, and antioxidant pathways within the skin, perhaps helping to keep

ROS-induced DNA damage at bay (Fig. 14.4). Most of the experimental work on

the skin role of the circadian clock has been performed in mice, which are nocturnal, while humans are diurnal. Therefore, a number of circadian clock-modulated

processes described in this review may exhibit antiphasic patterns in humans. It will

be important to take this fact into consideration when thinking about the implications of these findings in the realm of human physiology and disease.



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Fig. 14.4 Diurnal activities of circadian stress response pathways in the skin. In mouse skin,

circadian clock proteins, BMAL1 and CLOCK, exhibit peak expression during the night when

most epidermal progenitor cells are in S-phase and glycolysis is the predominant metabolic

pathway in these cells. The propensity for immune activation also peaks at night, which may help

defend against invading pathogens encountered during the active phase. Conversely, oxidative

metabolism and ROS production is higher during the day, coinciding with antioxidant pathway

activity. DNA damage repair also peaks during the day in mice



This chapter highlights the importance of the circadian clock in gating skin’s

stress response. In part, this notion is well supported by experimental data, but, in

part, the evidence is more speculative, pointing to the importance of further work in

this field. Circadian disruption, a common phenomenon in today’s society, may

impair the skin’s ability to handle stressors and infections.

Understanding the mechanisms by which the clock gates the skin’s responsiveness to external stimuli, as well as the physiological outcomes of this regulation, is of paramount importance for the development of chronotherapy.

Chronotherapy aims to administer drugs at specific times of the day to maximize the

beneficial effects of the treatment and/or to minimize side effects. For example,

5-fluorouricil treatment of tumor bearing mice wielded more potent anti-tumor

effects when dosed in the early morning compared to other times of the day (Kojima

et al. 1999). The pro-inflammatory effects of another anti-tumor/anti-viral drug, the

TLR7 agonist IMQ, have recently been shown to be diurnal with peak activity

induced after nighttime treatment in mice (Ando et al. 2015). Studies on skin active

drugs should consider time of day as a potentially important variable, modulating

effectiveness and side effects.



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4 Role of the Circadian Clock in the Skin’s Response to Endogenous and External Stressors

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